Caged agonist of P2Y1 and P2Y12 receptors for light-directed facilitation of platelet aggregation

Gao, Zhan‐Guo; Hechler, Béatrice; Besada, Pedro; Gachet, Christian

doi:10.1016/j.bcp.2007.10.037

Cited by 11 publications

(10 citation statements)

References 23 publications

(33 reference statements)

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“…However, in some cases, blocking the terminal phosphate moiety of a nucleoside 59-diphosphate or 59-triphosphate can lead to a great reduction in activity. For example, if the b-phosphate of the P2Y 1 /P2Y 12 agonist 2-methylthioadenosine 59-diphosphate (2MeSADP) is esterified with a photocleavable o-nitrobenzyl alcohol, receptor activity is lost (Gao et al, 2008).…”

Section: Toward a Systematic Characterization Of The Sar Of Dinucleotmentioning

confidence: 99%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y 2 and P2Y 11 ), ADP (P2Y 1 , P2Y 12 , and P2Y 13 ), UTP (P2Y 2 and P2Y 4 ), UDP (P2Y 6 and P2Y 14 ), and UDP glucose (P2Y 14 ). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the G i -coupled P2Y 12 R and two of the G q -coupled P2Y 1 Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 12 Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs.

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Section: Toward a Systematic Characterization Of The Sar Of Dinucleotmentioning

confidence: 99%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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“…from a triplicate determination representative of three independent experiments performed in duplicate or triplicate. The calcium mobilization was measured 20 s after addition of agonists and lasted for 120 s. The protocol used was similar to previously described [29]. The mean EC 50 values of agonists are listed in the text.…”

Section: Figuresmentioning

confidence: 99%

“…D. Schild analysis of antagonism by MRS2500 of the agonist effect of MRS2365. The calcium mobilization was measured 20 s after addition of agonists and lasted for 120 s. The protocol used for measurement of calcium mobilization was similar to previously described [29]. The EC 50 values (nM) of ADP and MRS2365 were 278 ± 42 and 4.5 ± 0.8 nM, respectively.…”

Section: Figuresmentioning

confidence: 99%

P2Y13 receptor is responsible for ADP-mediated degranulation in RBL-2H3 rat mast cells

Gao¹,

Ding²

2010

Pharmacological Research

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Extracellular ADP is known to play many important physiological roles. In this study, we identified the P2Y13 receptor in a rat mast cell line (RBL-2H3) and explored the functional role of ADP, its endogenous agonist. ADP induced both intracellular calcium mobilization and release of hexosaminidase (Hex). In an assay of intracellular calcium, ADP was 100-fold less potent than and equally efficacious as the P2Y1 receptor-selective agonist MRS2365. However, ADP was more potent and efficacious than MRS2365 in inducing Hex release and in enhancing antigen-induced Hex release. ADP-induced intracellular calcium mobilization was blocked by phospholipase C inhibitor U73122 and by P2Y1 receptor selective antagonist MRS2500, but not by pertussis toxin (PTX), suggesting a mechanism mediated by the Gq-coupled P2Y1 receptor, but not P2Y13 (Gi-coupled) or P2X receptors. ADP-induced Hex release was blocked by PTX and a selective P2Y13 receptor antagonist MRS2211, but not by MRS2500 or P2Y1 receptor-specific siRNA, suggesting a Gi-coupled P2Y13 receptor-related mechanism. Measurement of gene expression confirmed high expression of both P2Y1 and P2Y13 receptors (in comparison to a previously reported P2Y14 receptor) in RBL-2H3 cells. Thus, we demonstrated that ADP-mediated intracellular calcium mobilization and Hex release in RBL-2H3 cells are via P2Y1 and P2Y13 receptors, respectively. Selective antagonists of the P2Y13 receptor might be novel therapeutic agents for various allergic conditions.

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“…A caged form of ATP 69 , which regenerates ATP upon irradiation has been studied and is potentially useful for studies of P2Rs (Amatrudo et al ., 2015). Similarly, the 1-(3,4-dimethyloxy-6-nitro-phenyl)ethyl (DMNPE) group was used to block the β-phosphate of agonist 65 to abolish its activity at the P2Y 1 R and P2Y 12 R, and this activity could be recovered upon irradiation (Gao et al ., 2008). Such caged compounds are potentially useful for studying rapid neuronal responses to P2Y (or P2X) receptor activation.…”

Section: P2yr Modulatorsmentioning

confidence: 99%

Medicinal chemistry of adenosine, P2Y and P2X receptors

2016

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Pharmacological tool compounds are now available to define action at the adenosine (ARs), P2Y and P2X receptors. We present a selection of the most commonly used agents to study purines in the nervous system. Some of these compounds, including A1 and A3 AR agonists, P2Y1R and P2Y12R antagonists, and P2X3, P2X4 and P2X7 antagonists, are potentially of clinical use in treatment of disorders of the nervous system, such as chronic pain, neurodegeneration and brain injury. Agonists of the A2AAR and P2Y2R are already used clinically, P2Y12R antagonists are widely used antithrombotics and an antagonist of the A2AAR is approved in Japan for treating Parkinson’s disease. The selectivity defined for some of the previously introduced compounds has been revised with updated pharmacological characterization, for example, various AR agonists and antagonists were deemed A1AR or A3AR selective based on human data, but species differences indicated a reduction in selectivity ratios in other species. Also, many of the P2R ligands still lack bioavailability due to charged groups or hydrolytic (either enzymatic or chemical) instability. X-ray crystallographic structures of AR and P2YRs have shifted the mode of ligand discovery to structure-based approaches rather than previous empirical approaches. The X-ray structures can be utilized either for in silico screening of chemically diverse libraries for the discovery of novel ligands or for enhancement of the properties of known ligands by chemical modification. Although X-ray structures of the zebrafish P2X4R have been reported, there is scant structural information about ligand recognition in these trimeric ion channels. In summary, there are definitive, selective agonists and antagonists for all of the ARs and some of the P2YRs; while the pharmacochemistry of P2XRs is still in nascent stages. The therapeutic potential of selectively modulating these receptors is continuing to gain interest in such fields as cancer, inflammation, pain, diabetes, ischemic protection and many other conditions. Reported potencies refer to the human receptors unless otherwise noted. Additional affinity data can be found in recent review papers (Müller and Jacobson, 2011; Jacobson et al., 2015; Coddou et al., 2011a).

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Caged agonist of P2Y1 and P2Y12 receptors for light-directed facilitation of platelet aggregation

Cited by 11 publications

References 23 publications

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

P2Y13 receptor is responsible for ADP-mediated degranulation in RBL-2H3 rat mast cells

Medicinal chemistry of adenosine, P2Y and P2X receptors

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